- Host-Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism
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Renin-angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC). Complexes of candesartan and candesartan cilexetil with 2-hydroxylpropyl-β-cyclodextrin (2-HP-β-CD) were characterized using high-resolution electrospray ionization mass spectrometry and solid state 13C cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) spectroscopy. The 13C CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN's complexation, CAN exerts higher antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-β-CD is not indicated, while the formulation with CAN is promising and needs further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-β-CD, and thus, the molecule's availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy release for the drug to exert its bioactivity.
- Ntountaniotis, Dimitrios,Andreadelis, Ioannis,Kellici, Tahsin F.,Karageorgos, Vlasios,Leonis, Georgios,Christodoulou, Eirini,Kiriakidi, Sofia,Becker-Baldus, Johanna,Stylos, Evgenios K.,Chatziathanasiadou, Maria V.,Chatzigiannis, Christos M.,Damalas, Dimitrios E.,Aksoydan, Busecan,Javornik, Uro?,Valsami, Georgia,Glaubitz, Clemens,Durdagi, Serdar,Thomaidis, Nikolaos S.,Kolocouris, Antonios,Plavec, Janez,Tzakos, Andreas G.,Liapakis, George,Mavromoustakos, Thomas
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p. 1255 - 1271
(2019/02/26)
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- Method for treating azide ions, non-genotoxic impurity Sartan raw material medicine and immediate thereof
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The invention discloses a method for treating azide ions in a system and application thereof to the preparation of a compound with a tetrazolium group and without genotoxic impurities. The method is that the azide ions contained in the hydrogen peroxide treatment system are used. The method is used for preparing the compound with the tetrazolium group and comprises the following preparation steps:enabling a compound containing a cyano group to react with an azide, adding hydrogen peroxide after the reaction to quench and remove excessive sodium azide and further obtaining the compound with the tetrazolium group. The compound prepared by the method does not contain the genotoxic impurities. The method is simple in operation, mild in reaction conditions and suitable for industrial production.
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Paragraph 0105; 0106
(2019/05/28)
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- METHOD FOR PREPARING TRITYL CANDESARTAN
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The present invention uses a candesartan cyclic compound as a starting material and performs thereon a three-step reaction of forming tetrazole, hydrolysis and adding a protecting group to directly obtain trityl candesartan without separating an intermediate product via crystallization. The operating process is simple and thus is more applicable to industrial production.
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- A trityl protecting group by removing method of preparing losartan medicine
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The invention discloses a method for preparation of a Sartan drug by removal of a triphenylmethyl protective group. The method includes: under the catalysis of an insoluble weak acid, subjecting a Sartan prodrug and methanol to deprotection reaction, and after complete reaction, conducting aftertreatment to obtain the Sartan drug. The method has the characteristics of low cost, few side product, high quality product, and simple aftertreatment. At the same time, montmorillonite can be taken as insoluble weak acid, and the cost is low, thus being convenient for industrial production.
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Paragraph 0032-0039; 0047-0051
(2018/07/30)
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- Preparation method of candesartan
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The invention relates to a preparation method of candesartan. The preparation method comprises the steps of carrying out N-alkylation reaction, deprotection reaction and ester hydrolysis reaction on raw materials including 2-ethoxybenzimidazole-7-carboxylate and a tetrazole compound, so as to obtain the candesartan. According to the preparation method, compounds with high toxicity and large environmental protection pressure such as sodium azide, tributyl tin chloride or tributyl tin azide are not used; and compared with processes in the prior art, the preparation method is simple and convenient in operation and is beneficial to industrial large-scale production.
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- Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: Carboxymethylenebutenolidase and carboxylesterase 1
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Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In invitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM- and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM- and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL. Copyright
- Ishizuka, Tomoko,Yoshigae, Yasushi,Murayama, Nobuyuki,Izumi, Takashi
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p. 1888 - 1895
(2013/11/06)
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- PROCESS FOR PREPARATION OF CANDESART AN CILEXETIL SUBSTANTIALLY FREE OF DES-CANDESARTAN CILEXETIL IMPURITY
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The present invention provides a process for preparation of candeartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l-biphenyl]-4- yl]methyl]-l-[[(cyclohexyloxy)carbonyl]oxy]ethylester-lH-benzimidazole-7- carboxylate (des-candesartan cilexetil) impurity.
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- METHOD FOR ISOLATING 5-SUBSTITUTED TETRAZOLES
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The invention relates to a method for isolating 5-substituted tetrazoles of general formula (I) in which R represents a substituted biphenyl radical during which the ring closure, starting from a corresponding nitrile, is carried out in organic solvents while using alkali, alkaline-earth or organotin azides. The organic phases containing the nitrile and the tetrazol are firstly mixed with water while firstly forming three liquid phases, after which the aqueous phase containing the azide and the phase containing the nitrile are separated out, and the middle organic phase containing the tetrazol is subsequently processed. In the case of ester groups to be saponified, this phase is mixed with alkali lye, after which the organic phase is separated out and the aqueous phase is acidified or otherwise, this phase is immediately acidified and purified.
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Page/Page column 4
(2009/08/18)
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- PROCESS FOR PREPARATION OF CANDESARTAN CILEXETIL
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There was provided a process for preparing candesartan cilexetil, the said process comprises hydrogenating a solution of trityl candesartan cilexetil in an alcohol with hydrogen in the presence of a palladium catalyst. Mixture of toluene and methanol was added to 1-(Cyclohexyloxy carbonyloxy)ethyl-2-ethoxy-1-[[2'-(N-triphenylmethyltetrazole-5-yl)biphenyl-4-yl] methyl]benzimidazole-7-carboxylate and hydrogenated at room temperature with hydrogen at atmospheric pressure in the presence of palladium on carbon until the hydrogen uptake was ceased. Filtered over celite bed, washed the bed with a mixture of toluene and methanol, filtrate was collected and concentrated. Co- distilled with acetonitrile, acetonitrile was added, stirred at room temperature, cooled to 0°C. stirred, filtered, washed with chilled acetonitrile and dried to get candesartan cilexetil.
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Page/Page column 4
(2010/01/30)
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- ONE POT PROCESS FOR THE PREPARATION OF CANDESARTAN
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Present invention is to provide one pot synthesis of candesartan without isolating the ester intermediate.
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Page/Page column 5
(2008/06/13)
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- METHOD FOR OBTAINING BENZIMIDAZOLE DERIVATIVES AND INTERMEDIATES THEREOF
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The present invention relates to a method for obtaining benzimizadole derivatives and intermediates thereof, preferably, for obtaining Candesartan and Candesartan cilexetil. Said method allows the benzimizadole derivatives to be obtained with a higher yield.
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- PROCESS FOR PREPARING CANDESARTAN CILEXETIL
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A process for preparing candesartan cilexetil.
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Page/Page column 17
(2010/10/19)
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- CONVERSION OF AROMATIC NITRILES INTO TETRAZOLES
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The present invention relates to the conversion of aromatic nitriles to tetrazoles, comprising treatment of the cyano compound with trialkyltin chloride and sodium azide optionally in the presence of a phase transfer catalyst. The process is particularly useful in the perparation of Irbesartan,Candesartan, Losartan and Valsartan.
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Page/Page column 18
(2008/06/13)
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- CRYSTAL AND PROCESS FOR PRODUCING THE SAME
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A process for producing crystals of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimdazole-7-carboxylic acid (compound (I)), characterized by dissolving or suspending the compound (I) or a salt thereof in a solvent comprising an aprotic polar solvent and crystallizing it. By the process, the contaminants which are contained in the compound (I) or its salt and are difficult to remove, such as tin compounds, analogues of the compound (I), and a residual organic solvent, can be easily removed. Crystals of the compound (I) can be efficiently and easily mass-produced in high yield on an industrial scale.
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Page 19; 21-23
(2010/02/06)
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- Production method of aminobenzene compound
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The present invention is to provide an industrially useful production method of an aminobenzene compound represented by the formula: which is characterized by reacting a mixture of a mono-halogeno compound represented by the formula: and di-halogeno compound represented by the formula: with a compound of the formula:
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- Process for the production of tetrazolyl compounds
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Disclosed is a method for removing a protective group of an N-protected tetrazolyl compound which comprises reacting said N-protected tetrazolyl compound with a mineral acid under substantially anhydrous conditions in the presence of an alcohol, insuring a high reaction yield of the object tetrazolyl compound.
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- 1-(CYCLOHEXYLOXYCARBONYLOXY)ETHYL 2-ETHOXY-1-[[2'-(1H-TETRAZOL-5-YL)BIPHENYL-4-YL]METHYL]BENZIMIDAZOLE-7-CARBOXYLATE AND COMPOSITIONS AND METHODS OF PHARMACEUTICAL USE THEREOF
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1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-y l)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof has potent angiotensin II antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.
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- Nonpeptide Angiotensin II Receptor Antagonists. Synthesis and Biological Activity of Benzimidazolecarboxylic Acids
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A series of 2-substituted-1--1H-benzimidazole-7-carboxylic acids was prepared from the key intermediate 3-amino-2-amino>benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-methyl>-1H-benzimidazole-7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist.The AII antagonistic activity of the benzimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats.Most of the benzimidazoles showed high affinity for the AII receptor (IC50 value, 10-6-1--7 M) and inhibited the AII-induced pressor response at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753.The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor response suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipohilicity, and electronic effects affected the potency of the AII antagonistic action.Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect.The representative compound, 2-ethoxy-1-methyl>-1H-benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of AII to bovine adrenal cortical membrane with an IC50 value of 1.1*10-7 M.The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0*1--10 M).Oral administration of CV-11974 to conscious normatensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response.CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.
- Kubo, Keiji,Kohara, Yasuhisa,Imamiya, Eiko,Sugiura, Yoshihiro,Inada, Yoshiyuki,et al.
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p. 2182 - 2195
(2007/10/02)
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